The preparation of 7alpha-methyl-delta4,9,11-estratrienes

ABSTRACT

The preparation of 7 Alpha -methyl- Delta 4,9,11-estratrienes of the formula   WHEREIN R1 is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid of one to 18 carbon atoms and Y is selected from the group consisting of unsaturated aliphatic and halogenated unsaturated aliphatic radicals of two to four carbon atoms.

United States Patent Nedelec et al.

l 1*Sept. 12, 1972 [54] THE PREPARATION OF 7a-METHYL-A -ESTRATRIENES[72] Inventors: Lucien Nedelec, Clichy-sous-Bois, Seine-Saint Denis;Jean-Claude Gasc, Bondy, Seine-Saint Denis, both of France [73]Assignee: Roussel-Uclaf,Paris,France Notice: The portion of the term ofthis patent subsequent to June 21, 1983, has been disclaimed.

[22] Filed: Aug. 31, 1966 211 Appl. No.: 576,240

[30] Foreign Application Priority Data Sept. 3, 1965 France ..30381 [52]US. Cl. ..260/397.45, 23/364, 260/239.5,

260/239.55 R, 260/346.l, 260/397.3, 260/397.5, 260/488 B, 260/586 H,424/243 OTHER PUBLICATIONS Campbell et al., Steroids, Vol. 1, Mar. 1963,pp. 317- 324.

Velluz et a1., Comptes Rendus Acad. Sc. Paris, V. 257, No. 3, pp. 569-570.

Anner et al., Chimia, Vol. 20, Dec., 1966, pp. 434- 435.

Primary Examiner-Joseph Rebold Assistant Examiner-Ethel G. LoveAttorney-Hammond & Littell [5 7] ABSTRACT The preparation of7a-methyl-A" -"estratrienes of the formula O "CH3 wherein R is selectedfrom the group consisting of hydrogen and an acyl radical of an organiccarboxylic acid of one to 18 carbon atoms and Y is selected from thegroup consisting of unsaturated aliphatic and halogenated unsaturatedaliphatic radicals of two to four carbon atoms.

14 Claims, No Drawings THE PREPARATION OF 7a-METHYL-A"" ESTRATRIENES Theinvention further relates to novel therapeutic compositions.

The 7a-methyl-A- estratrienes of formula II are endowed with outstandinghormonal properties. For example, 70:,17a-dimethyl-A---estratriene-1713-01-3- one has marked androgenic andvery intense anabolic properties and in contrast to the l7-alkylandrogenic and anabolic compounds without a 7oz-methyl substituent, itmanifests only a very weak hepatonocivity. After a prolonged treatmentof rabbits, the amount of serous transaminases were found only slightlymodified and therefore, it can be concluded that the danger of a hepaticcytolysis is practically discarded. Also, 7amethyllja-ethynyl-A'-estratrieneljp-olfi-one has very marked hypocholesterolemiantproperties and a very attenuated degree of estrogenic activity, whichmakes it possible to utilize the product for a prolonged period of timein therapy for humans without any undesirable secondary effects. Inparticular, the rat unit determined by the Allen-Doisy test is amplysuperior with 5 mg. Furthermore, the said product possesses a favorableaction on the reduction of fecundity in the animal and displays veryintense anti-estrogenic properties. Therefore, the insertion of themethyl in the 7a-position in the molecule of l7a-hydrocarbonyl-[3"--estratriene-17B-OR,-3-ones has the effect of substantially modifyingthe nature of the physiological activity in the basic molecule. Theintensity of the action is not found modified by the insertion of thissubstituent, but the nature of the effect is found changed by theobvious attenuation or disappearance of the androgenic or estrogeniceffects depending upon the character of the hydrocarbon substituent inthe 170:- position.

OBJECTS OF THE INVENTION It is an object of the invention to provide thenovel 7a-methyl-A" "-estratrienes of formula I.

It is another object of the invention to provide a novel process for thepreparation of 7a-methyl-A-" estratrienes of formula II.

It is a further object of the invention to provide novel therapeuticcompositions.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION The novel 7a-methyl-A- -estratrienes of the invention havethe formula The acyl radical of the organic carboxylic acid having oneto 18 atoms may be derived from an aliphatic, aromatic, cycloaliphaticor heterocyclic carboxylic acid. Examples of suitable acids are alkanoicacids, such as formic acid, acetic acid, propionic acid, butyric acid,isobutyric acid, valeric acid, isovaleric acid, trimethyl acetic acid,caproic acid, B-trimethyl propionic acid, heptanoic acid, caprylic acid,pelarginic acid, capric acid, undecylic acid, lauric acid, myrisn'cacid, palmitic acid and stearic acid; alkenoic acids, such asundecylenic acid and oleic acid; cycloalkyl carboxylic acids, such ascyclopentyl carboxylic acid, cyclopropyl carboxylic acid, cyclobutylcarboxylic acid and cyclohexyl carboxylic acid; cycloalkyl alkanoicacids, such as cyclopentyl acetic acid, cyclohexyl acetic acid,cyclopentyl propionic acid and cyclohexyl propionic acid; arylalkanoicacids, such as phenyl acetic acid and phenyl propionic acid; arylcarboxylic acids, such as benzoic acid and 2,4-dinitrobenzoic acid;phenoxy alkanoic acids, such as phenoxy acetic acid, pchlorophenoxyacetic acid, 2,4-dichlorophenoxy acetic acid, 4-ter-butylphenoxy aceticacid, 3-phenoxy propionic acid and 4-phenoxy butyric acid; heterocycliccarboxylic acids, such as furane-Z-carboxylic acid,S-terbutylfurane-Z-carboxylic acid, S-bromofurane-Z-carboxylic acid andnicotinic acids; B-ketoalkanoic acids, such as acetylacetic acid,propionylacetic acid and butyrylacetic acid; amino acids, such asdiethylaminoacetic acid and aspartic acid.

Examples of Y are alkenyl radicals such as vinyl, al-

lyl, etc.; alkynyl radicals such as l-propynyl, 2'-propynyl, ethynyl,butynyl, etc., and halogenated alkenyl and alkynyl such astrifluorovinyl, chloroethynyl, etc.

Examples of compounds of formula I with valuable physiologicalproperties are l7a-vinyl-7a-methyl-A -estratrienel7B-ol-3-one endowedwith anabolisant properties; I7a-allyl-7a-methyl-A -estratriene-l 7B-ol-3-one endowed with progestomimetic properties; 1 7a-( 1'-propynyl)-7a-methyl-A- -"-estratriene- 1 7B- ol-3-one endowed withclaudogenic properties; l7a-(2 '-propynyl )-7a-methyl-A- "-estratrienel7B-ol-3-one endowed with hypophysial inhibitive properties;(trifluorovinyl)-7a-methyl-A" -estratrienel 7B-ol-3- one endowed withprogestomimetic properties; 173- acetoxy-l 701-ethynyl-7az-methyl-M--estratriene-3 one endowed with hypercholesterolemiant properties; andl7B-capryloxy-l 7a-ethynyl-7a-methyl-A -estratriene-3-one endowed withanti-estrogenic properties.

The novel process of the invention for the preparation of 7a-methyl-N'-estratrienes of the formula comprises subjecting a S-lower alkyleneketal-l7B- acyloxy-deseA-A -estrene wherein the acyloxy is derived froman organic carboxylic acid of one to 18 carbon atoms to hydration toform the corresponding 5-lower alkyleneketal-l7B-acyloxy-des-A-estrane-ll a-ol, subjecting the latter to acidhydrolysis to form l7B-acyloxy-desA-estrane-l la-ol-S-one, reacting thelatter with a formylation agent to form 1la-formyloxyl7B-acyloxy-des-A-estrane-5-one, brominating the latter toform 6-bromo-l la-formyloxy-l7B-acyloxydes-A-estrane-S-one,dehydrobrominating the latter to form 1la-formyloxy-17B-acyloxy-des-A-M-estrene-S- one, which can be saponifyedunder alkaline conditions to forml7B-acyloxy-des-A-A-estrene-l1a-ol-5-one, reacting the latter or the 1la-formyloxy derivative with a methyl magnesium halide in the presenceof a copper salt to form 7a-methyl-l7B-acyloxy-des-A-estrane-l la-ol-5-one, reacting the latter with an esterifying derivative of anorganic sulfonic acid to form 7a-methyl-l laorganosulfonyloxy-l7B-acyloxy-des-A-estrane-S-one,

reacting the latter with a lithium halide in the presence of a diloweralkyl formamide to form 7a-methyl-17B- acyloxy-des-A-A -estrene-5-one,saponifying under all7fl-ol-5-one, oxidizing the latter to form7a-methyldes-A-A-estrene-5,l 7-dione, reacting the latter with asecondary amine to form the corresponding 5- enamino-7a-methyl-des-A-A"-estradiene-l7- one, condensing the latter with l,3-dichlorobutene-2 toform 3-chloro-7a-methyl-4,5-seco-A -estradiene- 5,17-dione, hydrolyzingthe latter under acid conditions to form7a-methyl-4,5-seco-A-estrene3,5,l7- trione, cyclizing the latter in thepresence of a secondary amine to form 3-enamino-7a-methyl-A"--estratrienel7-one, subjecting the latter to acid hydrolysis to form7a-methyl-A -estradiene-3,17-dione, reacting the latter with aketalizing agent to form 3-dialkoxy-7a-methyl-A" -estradienel 7-one,reacting the latter with an organo metal compound to form3-dialkoxy-7a-methyll 7a-X-A -estradiene 1 7B- ol, wherein X has theabove definition, subjecting the latter to acid hydrolysis to form7a-methyl-17a-X- co sume- ZfiQbi-Qt and a n the latter with asubstituted p-benzoquinone to form 7amethyl- 1 7a-X-A"'-estratrienel7B-ol-3-one, which may be reacted with an acylating agent of an organiccarboxylic acid of one to 18 carbon atoms to form 7akaline conditions toform 7a-methyl-des-A-A -estrene- 25 m hyl-l7a-X-l7B-acyl0xy-A-"-estratriene-3-one.

HOOO I U-OAc HCOO-- The reaction scheme is illustrated in Table I.

TABLE 1 Wherein R is a. lower alkylene, A is an aoyl radical of anorganic carboxylic acid of 1 to 18 carbon atoms, R" is an organicradical, the Rs may be lower alkyl or together with the nitrogen towhich they are attached form a 5- to 6-n1embcr hcterocyclic ring, ltsare lower alkyl and X has the above definition.

A preferred mode of the process of the invention comprises reacting5-ethylenedioxy-l7B-benzoyloxydes-A- A -estrene with diborane in thepresence of an ether such as tetrahydrofuran or ethyl ether followed bytreatment with hydrogen peroxide to form 5- ethylenedioxy- 17B-benzoyloxy-des-A-estranel 1 (1-01, treating the latter with a mineralacid such as hydrochloric acid in a lower aqueous alkanol to form17B-benzoyloxy-des-A-estrane-l la-ol-Sone, -ol-5-one, reacting thelatter with formic acid at elevated temperatures to form1la-formyloxy-l7B-benzoyloxy-des- A-estrane-S-one, reacting the latterwith bromine in an organic solvent such as chloroform, dioxane, aceticacid or dimethylfon'namide to form 65-bromo-l la-formyloxyl7B-benzoyloxy-des-A-estrane-5 -one, reacting the latter with a mixtureof lithium carbonate and lithium bromide to formlla-formyloxy-l7B-benzoyloxydes-A-M-estrene-S-one, saponifying thelatter with an alkali metal carbonate or bicarbonate such as potassiumcarbonate in an aqueous alkanol at elevated temperatures to form17B-benzoyloxy-des-A-A -estrene- 1 1B-ol-5-one, reacting the latter withmethyl magnesium bromide in an ether such as tetrahydrofuran in thepresence of a cuprous halide such as cuprous chloride to form 7a-methyll7B-benzoyloxy-des-A-estrane-l la -ol-5-one, reacting the latter with analkyl or aryl sulfonic acid chloride such as methane sulfonyl chlorideto form 7a-methyl-l la-organosulfonyloxy-l 7 B-benzoyloxy-des-A-estrane-S-one, reacting the latter with lithium bromidein the presence of dimethylform amide to form7a-methyl-17B-benzoyloxy-des-A-A -estrene-S-one, saponifying the latterwith an alkali metal hydroxide such as potassium hydroxide to form 70:-

0 methyl-des-A-A-estrene-l7B-ol-S-one, oxidizing the latter with chromicacid anhydride to form 7a-methylv des-A-A-estrene-5,l7-dione, reactingthe latter with a secondary amine such as pyrrolidine, piperidine,morpholine or dilower alkyl amines such as 45 diethylamine to form thecorresponding 5-enamino-7amethy-des-A-A -estradiene-17-one, condensingthe latter with 1,3-dichlorobutene-2 in dimethylformamide in thepresence of an alkali metal iodide such as potassium iodide to form3-chloro-7a-methyl-4,S-seco- 50 A*--estradiene-5,l7-dione, hydrolyzingthe latter in the presence of a strong mineral acid such as concentratedsulfuric acid to form 7a-methyl-4,5-secoA -estrene- 3,5,l 7-trione,cyclizing the latter in the presence of pyrrolidine to form3-pyrrolidyl-7a-methyl-A estratriene-l7-one, hydrolyzing the latter withacetic acid at room temperature in the absence of air to form mide toform 3-dilower alkoxy-7a -methyl-l7a-X-A -estradiene-173-01, hydrolyzingthe latter with aqueous acetic acid to form 7a-methyl-l 7a-X-A-estradiene-l7B-ol-3-one and reacting the latter with a Imethyl-17a-X-A- -estratriene-3-one.

The novel therapeutic compositions of the invention for warm-bloodedanimals are comprised of a 701- methyl-A"-estratriene of the formulawherein R is selected from the group consisting of hydrogen and an acylradical of an organic carboxylic acid of one to 18 carbon atoms and X isselected from the group consisting of alkyl of one to seven carbon atomsand unsaturated aliphatic and halogenated unsaturated aliphatic radicalsof two to four carbon atoms and a major amount of a pharmaceuticalcarrier. The compositions may be prepared in the form of injectable ordrinkable solutions or suspensions, in the form of ampoules or multipledose flacons, in the form of implants, tablets, coated tablets,sublingual tablets and suppositories. The said compositions may beadministered orally, perlingually, transcutaneously or rectally and theusual useful dose is 0.001 to 0.03 mg/kg per day in the adult, dependingupon the mode of administration.

1 7a-ethynyl-7a-methyl-A -estratrienel 73-01-3- one is useful for thetreatment of hypoestrogensis in women or it can be used to reduce theamount of fecundity in women as well as in the breeding of animals.

In the following examples, there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE I Preparation of 7a-methyll 7a-ethyny1-A""- estratrienel7B-o1-3-one Step A: Preparation of l la-formyloxyl 7B-benzoyloxy-des-A-estrane-S-one 1. Preparation of diborane:

1.2 liters of the etherate of boron trifluoride were introduced into 1.2liters of the dimethyl ether of diethylene glycol. The mixture waspurged by means of a stream of nitrogen, then within the space of onehour and at room temperature, 162 gm of finely ground sodium borohydridewere introduced and the mixture was heated at a temperature of 40 C. for1 hour. The diborane was liberated with 3.6 liters of tetrahydrofuran.Thus a solution of diborane was obtained titrating 8.3 to 9.8 gm per 100cc.

2. Hydration:

Into 3.6 liters of the diborane solution, prepared as described above,256 gm of S-ethylenedioxy-l 7B- benzoyloxy-des-A-A -estrene, describedin US. Pat. No. 3,120,544 were introduced and allowed to stand at roomtemperature for 36 hour. Thereafter the mixture was cooled to atemperature of -5 C. Slowly 350 cc of water were added thereto followedby the addition of the following mixture:

36 Be sodium hydroxide solution 350 cc Water 350 cc Ethanol 1050 ccNext, 1.8 liters of 1 10 volume hydrogen peroxide were slowly added tothe reaction mixture and the mixture was agitated for 1 hour at a lowtemperature. The mixture was then poured into a saturated aqueoussolution of sodium chloride and the liquid phase was extracted withmethylene chloride. The extracts were washed with a saturated solutionof sodium chloride and with water, then dried and evaporated to drynessunder vacuum. The residue obtained was purified by trituration inisopropyl ether, thus obtaining 213.5 gm of 5-ethylenedioxyl7B-benzoyloxy-des-A-estranella-ol. The product obtained had a meltingpoint of 152 C and a specific rotation [a] 20D +29 (c 1 percent inchloroform).

The product is colorless, insoluble in water and slightly soluble inisopropyl ether.

3. Hydrolysis:

330 gm of S-ethylenedioxy-l7B-benzoyloxy-des-A- estrane-l 1121-01 weredissolved in 1,650 cc of ethanol while heating at a temperature of 60 C.Then 330 cc of N hydrochloric acid were introduced into the solution,which was heated at reflux for 15 hour under agitation. Thereafter, thesolution was cooled to room temperature, poured into water and extractedwith methylene chloride.

The extracts were washed first with a saturated aqueous solution ofsodium bicarbonate, then with water, dried, vacuum filtered, againwashed with water and evaporated to dryness. The residue was dissolvedin anhydrous ether under reflux and the crystallization was initiated.The crystallizing mixture was left in the refrigerator overnight, thenvacuum filtered. The crystals were washed with ether and dried to obtain240 gm of 17/3-benzoyloxy-des-A-estrane-l la-ol-S-one, having a meltingpoint of 129-130 C.

The product was colorless, insoluble in water and in dilute aqueousacids and alkalis, and soluble in alcohol and ether.

4. Formylation:

2.5 gm of 17B-benzoyloxy-des-A-estrane-1la-ol-S- one were introducedinto 12.5 cc of 98 percent formic acid and the solution was heated for khour at a temproduct had a melting point of C and a specific rotation[a]' =+l0.7 (c 0.7 percent in methanol) and +8.6 (c 0.44 percent inchloroform).

The product was colorless, insoluble in water and in dilute aqueousacids. It was recrystallized from isopropanol and isopropyl ether.

Analysis: c,,n,,o,; molecular weight 370.43 Calculated: C 71.33% H 7.07%Found: 71.6 7.1

Step B: Preparation of lla-formyloxy-17B-benzoyloxydes-A-A-estrene-5-one l. Bromination:

At room temperature, 100 gm of lla-formyloxy-17B-benzoyloxy-desA-estrane-S-one were dissolved in 1 liter of anhydrousdioxane. Within the space of 5 minutes, 460 cc of a solution containingpercent of bromine in dioxane were added thereto, and the solution wasagitated for several minutes after the introduction had been completed.

Thereafter, the solution was poured over an icewater mixture, agitatedand vacuum filtered. The residue was washed with water and dried undervacuum. Thus, 122 gm of 6-bromo-lla-formyloxyl7B-benzoyloxy-des-A-estrane-5-one were obtained. Theproduct had a melting point of about 94 C. and was used as such for thefollowing step.

2. Dehydrobromination 122 gm of lithium bromide and 244 gm of lithiumcarbonate were introduced into 1,220 cc of anhydrous dimethylformamide.122 gm of 6f-bromo-l la-formyloxyl 7B-benzoyloxy-des-A-estrane-5-oneobtained in the preceding, were added and the suspension was heated atabout 106 C for 3 hours under agitation.

Thereafter, the reaction mixture was cooled to room temperature andpoured into the following mixture:

Water 12 liters Acetic acid 300 cc Sodium chloride 160 gm and agitatedfor V4 hour.

The reaction mixture was then vacuum filtered. The residue was washedwith water, taken up in methylene chloride and filtered. The organicphase was washed with water, dried and evaporated to dryness undervacuum. The residue was triturated in anhydrous ether, iced overnight,then vacuum filtered. The residue was washed with ether and dried undervacuum.

After recrystallization from an ethyl acetateisopropyl ether mixture,45.9 gm of l1a-formyloxy-17 B-benzoyloxy-des-A-A -estrene-5-one wereobtained. The product had a melting point of l37l 38 C and a specificrotation [011 19.2 (c 0.9 percent in chloroform).

The product was insoluble in water and in dilute aqueous acids andalkalis, slightly soluble in isopropyl ether, and soluble in alcohol andethyl acetate.

Step C: Preparation of 17/3-benzoyloxy-7a-methyl-des- A-estrane-l1a-ol-5-one 70 mg of cuprous chloride were introduced into a solution of7 millimoles of methyl magnesium bromide in cc of tetrahydrofuran. Thereaction mixture was agitated for /4 hour, cooled to a temperature of 0C. and within the spaced of 2 minutes, 2 millimoles of 1 la-formyloxyl7B-benzoyloxy-des-A-M-estrene-S- one, dissolved in 6 cc oftetrahydrofuran, were added thereto. The agitation was maintained atlOwtemperature for several minutes, then the reaction mixture was pouredinto a mixture of water, ice and hydrochloric acid. Thereafter themixture was extracted with methylene chloride. The extracts thusobtained were washed with water, dried and distilled to dryness undervacuum.

By subjecting the residue to chromatography through magnesium silicateand by elution with methylene chloride containing 0.5 percent ofmethanol, 194 mg of l7B-benzoyloxy-7a-methyl-des- A-estrane-lla-ol-5-ofie, were isolated. This product had, after recrystallizationfrom a 2:4 mixture of ethyl acetate and isopropyl ether, a melting pointof l55l5 6 C and a specific rotation [a] +20 (c 0.75 percent inchloroform).

The product occurred in the form of small colorless rods, slightlysoluble in ether and soluble in acetone, benzene and chloroform.

Analysis: H O molecular weight 356.44 Calculated: C 74.13% H 7.92%

Found: 74.0 8.0

The structure of l7B-benzoyloxy-7a-methyl-des-A- estrane-l la-ol-S-onewas confirmed by reducing the same to17B-benzoyloxy-7a-methyl-des-A-estrane-5a ,1 la-diol, prepared asdescribed in the following:

0.356 gm of l7B-benzoyloxy-7a-methyl-des-A-estrane-lla-ol-S-one wasdissolved in 8 cc of ethanol. 0.35 gm of Raney nickel containing 2percent of pa]- ladium was added to the solution, which was then purgedand agitated for a period of 6 hours under an atmosphere of hydrogen andat room temperature.

Thereafter, the catalyst was eliminated by filtration. The filtrate wasdistilled to dryness under vacuum, and the residue was crystallized bythe addition of a few drops of ether.

After trituration in isopropyl ether and after recrystallization fromethyl acetate, 0.178 gm of 178- benzoyloxy-7a-methyl-des-A-estrane-5a,lla-diol was obtained, having a melting point of 154C and a specificrotation [a] +3.7 (c 0.8 percent in chloroform).

The RMN spectra confirmed the a configuration of the methyl in the 7position.

The product was colorless, slightly soluble in ether and soluble inalcohol, acetone, benzene and chloroform.

17B-benzoyloxy-7 a-methyl-des-A-estrane-l 1 a-ol-S- one may also beprepared by starting with 173- benzoyloxy-des-A-A -estrenene- 1 1a-ol-S-one, obtained by saponification of the corresponding formate. Thework is carried out in the following manner:

1 gm of lla-formyloxy-l7B-benzoyloxy-des-A-A estrene-S-one wasintroduced into 15 cc of methanol and the solution was heated to reflux.Next, 5 cc of a normal aqueous solution of potassium bicarbonate wererapidly added thereto, and the temperature was maintained for 5 minutesat about C. Thereafter, the reaction mixture was cooled, neutralized bythe addition of acetic acid, diluted with water and extracted withmethylene chloride.

The extracts were successively washed first with water, then with anaqueous solution of sodium chloride, dried and distilled to dryness toobtain raw 1 7fl-benzoyloxy-des-A-A -estrene-l la-ol-S-one.

l7B-benzoyloxy-des-A-A -estrene-l la-ol-5 -one can also be prepared bystarting with l7B-benzoyloxy-des- A-estranel la-ol-S-one. The work isaccomplished in the following manner:

(a) Bromination 3 gm of l7B-benzoyloxy-des-A-estrane-l 1a-ol-5-one weredissolved in 30 cc of anhydrous chloroform. The solution cooled to about5 C. Next, under agitation, 9.5 cc of a solution prepared by startingwith 15.25 gm of bromine in cc of anhydrous chloroform were in troduceddropwise while cooling to C. The agitation was maintained for severalminutes after the introduction had been completed. Then, the reactionmixture was poured into water, decanted and extracted with methylenechloride.

The extracts were successively washed first with a saturated aqueoussolution of sodium bicarbonate, then with water and lastly with anaqueous solution of sodium chloride, and distilled to dryness undervacuum. The residue was taken up with ether and allowed to stand forseveral hours at room temperature. Thereafter, the residue was vacuumfiltered, washed with ether and triturated in ethyl acetate to obtain 1gm of 6fi-bromo-1 7B-benzoyloxy-des-A-estrane-1 1 01-016- one having amelting point of 225-228 C. and a specific rotation [a] 160" (0 0.8percent in chloroform).

The product was colorless, slightly soluble in ether and soluble inchloroform.

(b) Dehydrobromination A mixture consisting of 1 gm of lithium bromide,2 gm of lithium carbonate and 10 cc of dimethylformamide was heated to atemperature of 100 C. Then 1 gm of 6B-bromo-17B-benzoyloxy-des-A-estrane-l 101-01-5- one was introduced into thismixture and agitated for 3 hours at about 100 C. Thereafter, thereaction mixture was poured into a mixture of water, ice and aceticacid. Sodium chloride was added thereto and the mixture was agitated for56 hour. The aqueous phase was decanted and the resultant residue wasdissolved in methylene chloride.

The solution was successively washed first with an aqueous solution ofsodium bicarbonate, then with water and lastly with an aqueous solutionof sodium chloride, then dried and distilled to dryness under vacuum.The product thus obtained was subjected to chromotography through silicagel and eluted with methylene chloride containing increasing percentagesof methanol.

The fraction eluted with methylene chloride containing 1.5 percent ofmethanol was recovered, and 0.68

gm of 17B-benzoyloxy-des-A-A -estrene-lla-ol-S-one was isolated.

The product was colorless, slightly soluble in ether and isopropylether, soluble in ethyl acetate and a1- cohols.

Infrared Spectra (chloroform) Presence of a free hydroxyl and of aketonic group at 1,670 cm.

Ultraviolet spectra (ethanol) nmax. 230-231 my. g=23,000

max. 273-274 mp. g= 1,020 Amax. 280-281 mp. 780

was maintained for 15 minutes after the introduction had been completed.The reaction mixture was poured into ice water containing concentratedhydrochloric acid, and extracted with methylene chloride. The extractswere successively washed first with water, then with an aqueous solutionof sodium chloride, dried and distilled to dryness under vacuum. Theresidue was subjected to chromatography through magnesium silicate,followed by elution with methylene chloride containing 0.3 percent ofmethanol to obtain 1.2 gm of a crystallized product.

The recrystallization of the product obtained from methylene chloridewith addition of a 2:1 mixture of ether and isopropyl ether furnished1.07 gm of 178- benzoyloxy-7a-methyl-des-A-estrane- 1 1a-ol-5 -oneidentical to the produce described above.

Step D: Preparation of 17B-benzoyloxy-7a-methyl-des- A-A-eStrene-S-one 1. Esterification 0.865 gm ofl7fi-benzoyloxy-7a-methyl-des-A-estrane-l la-ol-S-one was dissolved in5.2 cc of anhydrous pyridine. The solution was cooled to about 0 C.,then 0.52 cc of methanesulfonyl chloride was added dropwise thereto. Thereaction mixture was then agitated for 2 more hours at room temperature,then for 2 more hours at room temperature. After dilution with water,the reaction mixture was allowed to stand for 1 hour at roomtemperature, then vacuum filtered. The residue was washed with water anddriedunder vacuum to obtain 1.037 gm of 1la-methanesulfonyloxy-17B-benzoyloxy-7a-methyl-des-A-estrane-5-one,which after recrystallization from ethanol, had a melting point of 214-215 C.

The product occurred in the form of colorless needles, slightly solublein alcohol and soluble in chloroform.

2. Dehydration 2.36 gm of l la-methanesulfonyloxy-7a-methyl-l7B-benzoyloxy-des-A-estrane-5-one, and 3.95 gm of lithium bromide wereintroduced into 35 cc of anhydrous dimethylformamide, and the mixturewas agitated for 5 hours at a temperature of C. Thereafter, it wascooled, poured into water, agitated for hour and vacuum filtered. Theresidue was washed with water and dried under vacuum. The resultantproduct, successively triturated first in ether and then in ethylacetate, supplied 1.412 gm of l7fl-benzoyloxy-7amethyl-des-A-A-estrene-5-one which, after recrystallization from ethyl acetate, had amelting point of 182183 C., then 200 C., after having recrystallized,and a specific rotation [a] 49.6 (c 0.48 percent in chloroform).

Ultraviolet Spectra (ethanol) Kmart. 236 mp, 26,200

Infrared Spectra (chloroform) Presence of a ketonic group at 1,667 cmPresence of a double bond at 1,615 cm Presence of a benzoate group at1,712 cm The product occurred in the form of small colorless rods,insoluble in water, very slightly soluble in ether, slightly soluble inalcohol and soluble in chloroform.

Analysis: C l-1, 0 molecular weight 338.43 Calculated: C 78.07% H 7.74%Found: 78.1 7.8

Step B: Preparation of 7a-methyl-des-A-A -estrene- 17B-ol-5 -one 0.272gm of l7B-benzoyloxy-7a-methyl-des-A-A -estrene-S-one were introducedinto 2.7 cc of methanol. 0.1 cc of a potassium hydroxide solution wasadded thereto, and the reaction mixture was heated at reflux for 1 hourunder an atmosphere of nitrogen. Thereafter, the reaction mixture waspoured into water and extracted with methylene chloride. The extractswere washed with water, dried and evaporated to dryness to obtain 0.185gm of 7a-methyl-des-A-A -estrene-l7B-ol-5-one with a melting point ofll9-l20 C. The product was utilized as such for the next step in thesynthesis.

The product occurred in the form of colorless prisms, insoluble in waterand in dilute aqueous acids and alkalis, and soluble in most of thecommon organic solvents.

Step F: Preparation of 7a-methyldes-A-A -estrene- 5,17-dione 10.7 gm of7a-methyl-des-A-A -estrene-l73-01-5- one were dissolved in 64 cc ofacetone. The solution was agitated, cooled to about C, then 12.3 cc ofthe following solution were added dropwise:

Chromic acid anhydride 67.5 gm

Sulfuric acid 57.5 cc

and water in sufficient quantity to obtain a solution of 250 cc. Thereaction mixture was agitated for 1 hour room temperature. Thereafter,the reaction mixture was poured into water. The solvent was removed. Icewas added to the mixture. The residue was vacuum filtered, washed withwater and dried to obtain 8.205 gm of 7a methyl-des-A-A -estrenel7-dione. The product, recrystallized from ethanol, had a melting pointof 140C and a specific rotation [a] +96.5 (c 0.45 percent inchloroform).

Ultraviolet Spectra (ethanol) A max. 240-241 mp. 13,400

The product was colorless, insoluble in water, in dilute aqueous acidsand alkalis, and soluble in most of the usual organic solvents.

Analysis: c l-i O molecular weight 232.31 Calculated C 77.55% H 8.68%Found: 77.3 8.8

Step G: Preparation of 5-pyrrolidyl-7a-methyl-des-A 13 -estradienel7-one Ultraviolet Spectra (ethyl ether) )tmax. 284 my. 9,975

The product was insoluble in water and in dilute aqueous acids andalkalis and soluble in most of the common organic solvents.

Step H. Preparation of 3-chloro-7a-methyl-4,5-seco- A -estradiene-5 ,17-dione While working under an atmosphere of nitrogen, 13.1 gm of5-pyrrolidyl-7amethyl-des-A-A ""estradiene-17-one were dissolved in 71.5cc of a 10.9 percent potassium iodide solution in dimethylformamide. Thesolution was cooled to a temperature of about 0 C. Then 12.7 cc of1,3-dichloro-2-butene were added thereto and the agitation wasmaintained for 2 hours at the low temperature. Thereafter, the reactionmixture was diluted with water, heated at a temperature of 90 C for aperiod of two and a half hours, cooled and finally extracted withmethylene chloride. The extracts were washed with water, dried andevaporated to dryness. The residue was subjected to chromatographythrough magnesium silicate with elutions with methylene chloride toobtain 14.4 gm of 3-chloro-7amethyl-4,5-seco-A -estradiene-5 l 7-dione,which product was used as such for the next step in the synthesis.

Ultraviolet Spectra (ethanol) Amax. 249 -250 my. 9,450

The product was insoluble in water and in dilute aqueous acids andalkalis, and soluble in most of the usual organic solvents.

Step 1: Preparation of 7a-methyl-4,5-seco-A -estrene- 3,5,l7-trioneWhile working under an atmosphere of nitrogen, 14.4 gm of3-chloro-7a-methyl-4,5-seco-A -estradiene-5,17-dione were dissolved incc of methylene chloride. The reaction mixture was cooled to about 0 C.Then 70 cc of sulfuric acid were added dropwise and the mixture wasagitated for 15 minutes at a temperature of about 0 C. Thereafter, thereaction mixture was cooled to a temperature of -10 to 15 C and veryslowly water was added. The mixture was then diluted with methylenechloride. The organic phase was separated, washed with water, dried andevaporated to dryness. The residue was subjected to chromatographythrough magnesium silicate with elutions with methylene chloridecontaining increasing amounts of acetone. The fractions, eluted withmethylene chloride containing 2 and 3 percent of acetone, were combined,filtered and evaporated to dryness to obtain 8.338 gm of7a-methyl-4,5-seco-A estrene-3,5,l7-trione, which was utilized as suchfor the next step in the synthesis.

Ultraviolet Spectra (ethanol) )tmax. 252 mp. 10,690 The product wasinsoluble in water, and in dilute aqueous acis and alkalis, and solublein most of the usual organic solvents.

Step .1: Preparation of 3-pyrrolidyl-7a-methyl- A -"estratriene-l 7-oneWhile working under an atmosphere of nitrogen, 9.812 gm of7a-methyl-4,5-seco-A -estrene-3,5,17- trione were dissolved in 45 cc ofanhydrous methanol, then 4.5 cc of anhydrous pyrrolidine were added andthe mixture was agitated for 20 hours. Thereafter, the reaction mixturewas cooled for 1 hour at a temperature of l0 C. Then it was vacuumfiltered. The residue was washed with iced methanol and dried to obtain7.457 gm of 3-pyrrolidyl-7a-methyl-A estratriene-l 7-one, having amelting point of 156 C.

3 ,69 1 ,2 15 '15 |6 The product occurred in the form of needles,insoluture at 50 C was maintained. The agitation and the ble in waterand in dilute aqueous acids and alkalis bubbling of inert gas weremaintained; then the reacslightly soluble in methanol and ethanol, andsoluble in tion mixture was agitated for 4 more hours at 40 C ether,benzene and chloroform. while passing a current of acetylenetherethrough.

wow) u 5 Then 3.5 gm of ammonium chloride were introduced Step K1Preparation of7amethylA into the reaction mixture and the temperaturewas 3,17*dine raised to 0 C and the ammonia was removed. After 30 whileworking under an atmosphere f nitrogen, cc of water were added thereto,the reaction mixture 7 777 gm of 3 fi l 7 h A8.5(10).9(ll) was extractedwith methylene chlor de and the organlc tratriene-l7-one were dissolvedin cc of acetic acid; Phase was washed E water mm] the wash waters thenat room temperature 200 cc of water were added were neutral f dnedfikered and evaporate? to and the reaction mixture was allowed to standfor- 2 dryness to obtam gm a raw ethynyl denvatlve' hours. Next thereaction mixture was iced for l-hour Thg raw produFt 'f? purified by qat y and vacuum filtered. The residue was washed with Fhmugh {nagnesmmand recrystalhzauon fl water and dried to obtain 5.2 gm of 7a-methyl-Al5 lsopropyilc ether to obtam 52 (69 fifgfg fi -estradiene-3,l7-dione.The product, passed of :is'dlmethoxyqmnethyl'l7aethynyl' D throughmagnesium silicate and recrystallized from fi i the form of solidcolorlgss isopropyl ether, had a melting point of 141 C and a pro Solube m h orgamc solvents and Specific rotation [011201) +2720 (c 075percent in soluble ln water and m dllute aqueous acids and alkalls.

. o chloroform) The product obtained had a melting polnt of 130 C.

Ultraviolet Spectra (ethanol) Infrared Spectra Absence of C 0 Amax 2415: lgoso Presence of 01-1 at 3,590 cm The product occurred in the formof colorless nee- Presence of C I CH at 3300 -1 dles, insoluble in waterand in dilute aqueous acids and Presence of 2 conjugated C bands at1,643 cmalkalis, and soluble in most of the common organic soland 1,612cm. vents.

Step N: Preparation of 7a-methyl-l7a-ethynyl- Analysis: C,.H,.0,;molecular weight 284.38 A -eSIradiene- 1 73-01-3 -one al I d: c 80.24% H8.50% 5 3 81 6.1 gm of 3,3 -dlmethoxy-7a-methyll 7a-ethynyl-A-estradiene-1718-01 were suspended in 30 cc of acetic acid containing 5per cent of water and the solution was agitated for 15 minutes at roomtemperature under an inert atmosphere. Then, 15 cc of water were whileworking under an atmosphere of nitmgen, 5 added to the solution, whichwas again agitated for 15 gm of 5 l0),9(11) were minutes. Still at roomtemperature and under an inert dissolved in 2.5 cc of methanol. 0.125 ccof a 0.07 N P 300 cc of a Saturated aqueous i n of hydrochloric acidsolution in methanol was added and 40 f blcarbonate Slowly added and hemixture the reaction mixture was allowed to stand for 1 hour at was formlnules and en filtered. The room temperature. Next, the reactionmixture was preclpltat? obtamed was Vacuum ered, washed with placed inthe refrigerator for 2 hours, then vacuum filwater the wash Waters wereutral and dried tered. The residue was washed with water and dried to gg to otftam 52 gm of hyl-l7a-ethy- Obtain 525 mgm of 3 st10mm1) nyl-A:estradlene-l7B-ol-3-one having a melting estradiene-l7-one. Afterrecrystallization from pmm of 226 Q Step L: Preparation of3,3-dimethoxy-7a-methyl- 3 5 Am0),9(11)B-eatraatene-1 7 methanol, theproduct had a melting point of 15 0 C This compound occurred in the formof colorless and a Specific rotation 20 (c 0.83 percent crystalllneneedles, whlch were soluble in the usual orv chloroform). ganlc solventsand insoluble in water and in dilute aqueous acids and alkalis.

Ultraviolet Spectra (ethanol) Ultra-Violet Spectra (ln ethanol)inflection toward 237 my. g, 1% 6) 243 g ZOOSO Amax 241-242 mg. 52 630The product was colorless, insoluble ln water and in inflecqon award 250m; 440

dilute aqueous alkalls, and soluble ln most of the com- 55 inflection toa d 290 nm g =4.7

mon organic solvents.

This spectra characterized a heteroannular diene. Step M: Preparation of3,3-dimethoxy-7a-methyl- 1 7aethynyl-A "estradiene-l 73-01 InfraredSpectra (chloroform) 105 cc of ammonia were cooled to -50 C and thenPresence of OH at 3,590 1.750 gm of potassium were added thereto underagitae e e OfC CH at 3,300 cm'L. tion and bubbling of inert gas and acurrent of Presence of non-Conjugated ketone acetylene was passedthrough the reaction mixture for 4,9, 30 minutes. The precipitateobtained was diluted with Step Preparami z i i 137aethynyl A 28 cc ofether and then 28 cc of ether and 7 gm of 3,3- es fa nene'dimethoxy-7a-methyl-A "-estradiene-17-one 4 gm of7a-methyl-l7a-ethynyl-A -estradienewere added to the reaction mixtureand the tempera- 17B-ol-3-one, cc of dichloroethane and then 8 gm of2,3-dichloro-5,-dicyano-p-benzoquinone were successively introduced intoa three-neck flask under an inert atmosphere. The mixture was maintainedunder agitation for 20 hours at room temperature, after which thehydroquinone was separated and washed with dichloroethane. Next, thecombined dichloroethane phases were washed first with a sodiumbicarbonate solution, then with sodium bisulfite and finally withaqueous sodium chloride. The organic solution was dried, filtered andbrought to dryness to obtain 3.6 gm of raw product, which was purifiedthrough silica gel and eluted with a mixture of chloroform and ethylacetate. The eluate was dried and the residue obtained wasrecrystallized from a minimum of refluxing ethanol, then crystallized,iced, vacuum filtered, washed with water and dried to obtain a firstyield of 595 mg of product having a melting point of 214C. Theconcentration of the mother liquors yielded a further 197 mg of theproduct.

For the purpose of analysis, the product was once more recrystallizedfrom ethanol at high and low temperatures.

The product, which, was 7a-methyl-l7a-ethynyl- A-estratriene-I7B-ol-3-one occurred in the form of colorless needles,which were soluble in alcohol, ether, acetone, benzene and chloroform,and insoluble in water. The said product had a melting point of 215 Cand a specific rotation [a =38 (c 0.5 percent in methanol).

Ultra-violet Spectra (in ethanol) )rmax. 238 mp. E 202 inflection toward271 my. E 123 Mnax. 243 my. 930 g 28.700)

This compound is not described in the literature.

EXAMPLE 11 Preparation of 7a,17a-dimethyl-A -estratriene-l 7B- ol-3-oneStep A: Preparation of 3,3-dimethoxy-7a,l7adimethyl-A-estradiene-1713-01 1.732 gm of 3,3-dimethoxy-7a-methyl-A-estradiene-l7B-one, (obtained in Step L of Example 1) dissolved in 90cc of anhydrous benzene were added to 110 cc of a 2.3 M titratingsolution of magnesium methyl bromide in ether and cooled to about Cwithin the space of 20 minutes. The reaction mixture was agitated for 20hours at room temperature. Then the reaction mixture was poured into asaturated aqueous solution of ammonium chloride, iced, decanted, thenwashed with water until the wash waters were neutral, dried and finallyevaporated to dryness under vacuum to obtain 2.045 gm of3,3-dimethoxy-7a,17adimethyl-A -estradiene-l7B-ol, which product wasused as such for the next step of the synthesis.

Ultra-Violet Spectra (in ethanol) Amax. 243 my. f= 17,400

The product was insoluble in water and in dilute aqueous acids andalkalis, and soluble in most of the common organic solvents.

Step B: Preparation of 7a,l7a-dimethyl-A estradiene-l 7B-ol-3-one 2 gmof 3,3-dimethoxy-7a,l7a-dimethyl-A estradiene-17B-ol were introducedunder an inert atmosphere into 10 cc of a 5 percent acetic acidsolution. The mixture was agitated for 15 minutes and after 5 cc ofwater were added, the agitation was continued for 15 minutes more. Thenthe reaction mixture was slowly poured into a saturated solution ofsodium bicarbonate and extracted with methylene chloride. The extractobtained was washed with water, dried, evaporated to dryness to obtain1.77 gm of 7a, 1 7a-dimethyl-A -estradiene-l7B-ol-3-one. This compoundwas used as such for the next step of the synthesis.

Ultra-Violet Spectra (in ethanol) MAX. 241 mp. 14,900

The product was insoluble in water and in dilute aqueous acids andalkalis and soluble in most of the usual organic solvents.

Step C. Preparation of 7a, 1 7a-dimethyl-A estratriene l7B-ol-3-oneUnder agitation and under an atmosphere of nitrogen, 1.6 gm of701,17a-dimethyl-A -estradiene-l7B-ol-3-one was dissolved in 32 cc ofanhydrous dioxane, then 2.4 gm of 2,3-dichloro-5,6-dicyano-pobenzoquinone were added thereto, and the reaction mixture wasallowed to stand for 28 hours at room temperature. Thereafter, themixture was filtered, and the filtrate was washed first with a saturatedaqueous solution of sodium bicarbonate and then with water. The organicphase was dried and evaporated to dryness. The residue was taken up withmethylene chloride and filtered through magnesium silicate.

The filtrate, evaporated to dryness, was subjected to chromatographythrough magnesium silicate with elution with methylene chloridecontaining 2 percent of acetone. The eluate was evaporated to dryness.The residue was crystallized from ethanol to obtain mgm of7a,17a-dimethyl-A -estratriene-l7B-ol-3- one, having a melting point of173 C and a specific rotation [a] =l 25 (c 0.57 percent in methanol).

The product occurred in the form of prisms which were insoluble in waterand in dilute aqueous acids and alkalis, and soluble in most of thecommon organic solvents.

Analysis: C,,,l-l,,0,; molecular weight 298.41 Calculated: C 80.49% H8.78% Found: 80.5 8.7

Ultra-Violet Spectra (ethanol) Amax. 343 my. 27,800 Variousmodifications of the compositions and process of the invention may bemade without departing from the spirit or scope thereof, and it is to beunderstood that the invention is to be limited only as defined in theappended claims.

We claim:

1. A process for the preparation of 7a-methyl-A 4,9,1 l-estratrienes ofthe formula wherein X is selected from the group consisting of alkyl ofone to seven carbon atoms and unsaturated aliphatic and halogenatedunsaturated aliphatic radicals of two to four carbon atoms whichcomprise subjecting a lower alkylene ketal-l7B-acyloxy-des-A-A 'estrenewherein the acyloxy is derived from an organic carboxylic acid of one to18 carbon atoms to hydration to form the corresponding 5-lower alkyleneketal-l7B- acyloxy-des-A-estrane-l la-ol, subjecting the latter to acidhydrolysis to form 17B-acyloxy-des-A-estrane-ll a-ol-5-one, reacting thelatter with a formylation agent to form 1 la-formyloxy-l7B-acyloxy-des-A-estrane-S- one, brominating the latter to formg-bromo-l la-formyloxy- 1 7B-acyloxy-des-A-estrane-5-one,dehydrobrominating the latter to form lla-formyloxyl7B-acyloxy-des-A-Aestrene-5-one, which can be saponifyed under alkaline conditions to form17B- acyloxy-des-A-A -estrene-l la-ol-Sone, reacting the latter or thella-formyloxy derivative with a methyl magnesium halide in the presenceof a copper salt to form 7a-methyll 7B-acyloxy-des-A-estrane-l la-ol-5one, reacting the latter with an esterifying derivative of an organicsulfonic acid to form 7a-methyl-l la-organosulfonyloxyl7B-acyloxy-des-A-estrane-5one, reacting the latter with a lithium halidein the presence of a dilower alkyl formarnide to form 7a-methyl-l7B-acyloxy-des-A-A -estrene-5one, saponifying the latter under alkalineconditions to form 7a-methyl-des-A-A- estrene-l7fi-ol-5one, oxidizingthe latter to form 70:- methyl-des-A-A -estrene-5 ,l 7-dione, reactingthe latter with a secondary amine to form the corresponding 5-enamino-7a-methyl-des-A-A -estradienel 7- one, condensing the latterwith 1,3-dichlorobutene 2 to form 3-chloro-7a-methyl-4,5-seco-A-estradiene- 5,17-dione, hydrolyzing the latter under acid conditions toform 7a-methyl-4,5-seco-A-estrene-3,5,l7- trione, cyclizing the latterin the presence of a secondary amine to form 3-enamino-7a-methyl-A-estratriene-l7-one, subjecting the latter to acid hydrolysis to form7a-methyl-A -estradiene-3,l7-dione, reacting the latter with aketalizing agent to form 3-dialkoxy-7a-methyl-A -estradienel 7-one,reacting the latter with an organo metal compound to form3-dialkoxy-7a-methyl-l 7a-X-A"""-estradiene-l 7/3- 01, wherein X has theabove definition, subjecting the latter to acid hydrolysis to form7a-methyl-l7a-X- A -estradiene-l7B-ol-3-one and reacting the latter witha substituted p-benzoquinone to form 70:- methyl- 1 7a-X-A""-estratriene-1 7B-ol-3-one.

2. The process of claim 1 wherein the 7a-methyl-l7 a-X-A"-estratriene-l7/3-ol-3-one is reacted with an esterifying agent of anorganic carboxylic acid of one to 18 carbon atoms to form thecorresponding 7a-methyll 7a-X- 1 7 fl-acyloxy-N' "-estratriene-3-one.

3. The process of claim 1 wherein the 5-lower alkyleneketal-l7B-acyloxy-des-A- -estrene is reacted with diborane in an etherfollowed by reaction with hydrogen peroxide.

5 4. The process of claim 3 wherein the l7B-acyloxy- ,des-A-estrane-lla-ol-S-one is reacted with formic acid at elevated temperatures. Y

5. The process of claim 1 wherein the lla-formyloxy-l7B-acyloxy-des-A-estrane-S-one is reacted with bromine inan inert solvent and the 6-bromo-l la-formyloxy-l7B-acyloxydes-A-estrane-5 -one is dehydrobrominated with a mixture oflithium carbonate and lithium bromide.

6. The process of claim 1 wherein the lla-formyloxyl7B-acyloxy-des-A-M-estrene-S-one is reacted with an alkaliselected from the group consisting of alkali metal carbonates andbicarbonates in hot aqueous methanol.

7. The process of claim 1 wherein the l7B-acyloxydes-A-N-estrene-lla-ol-S-one is reacted with a methyl magnesium halide in the presence ofa cuprous halide.

8. The process of claim 1 wherein the 7a-methyl-l7B-acyloxy-des-A-estrane-l la-ol-S-one is reacted with methane sulfonylchloride to form 7a-methyl-l1amethane-sulfonyloxy-l7B-acyloxy-des-A-estrane-S- one which is reactedwith lithium bromide in dimethylformamide.

9. The process of Claim 1 wherein the 7a-methyl-l 7B-acyloxy-des-A-A-estrene-5-one is reacted with an alkali metalhydroxide to form 7a-methyl-des-A-A -estrene-17B-ol-5-one which is thenoxidized with chromic anhydride.

10. The process of claim 1 wherein 7a-methyl-des-A- A-estrene-5,l7-dioneis reacted with a compound selected from the group consisting ofpyrrolidine, piperidine, morpholine and dilower alkylamines and theresulting 5-enamino-7a-methyl-des-A-A"-estrenel7-one is condensed with1,3-dichlorobutene-2in dimethylformamide in the presence of an alkalimetal iodide.

11. The process of claim 1 wherein 7a-methyl-4,5-seco-A-estrene-3,5,l7-trione is cyclized with pyrrolidine.

12. The process of claim 1 wherein 7oz-methyl-A -estradeiene-3,17-dioneis reacted with methanol in the presence of hydrochloric acid.

13. The process of claim 1 wherein the 3-diloweralkoxy-7a-methyl-A-eStradiene-l7-one is reacted with potassium acetylide.

14. The process of claim 1 wherein 7a-methyl-l7a- X-A-estradiene-I7B-ol-3-one is reacted with2,3-dichloro-5,o-dicyano-p-benzoquinone.

a: a: a: a: a:

2. The process of claim 1 wherein the 7 Alpha -methyl-17 Alpha -X- Delta4,9,11-estratriene-17 Beta -ol-3-one is reacted wiTh an esterifyingagent of an organic carboxylic acid of one to 18 carbon atoms to formthe corresponding 7 Alpha -methyl-17 Alpha -X-17 Beta -acyloxy- Delta4,9,11-estratriene-3-one.
 3. The process of claim 1 wherein the 5-loweralkylene ketal-17 Beta -acyloxy-des-A- Delta 9(11)-estrene is reactedwith diborane in an ether followed by reaction with hydrogen peroxide.4. The process of claim 3 wherein the 17 Beta -acyloxy-des-A-estrane-11Alpha -ol-5-one is reacted with formic acid at elevated temperatures. 5.The process of claim 1 wherein the 11 Alpha -formyloxy-17 Beta-acyloxy-des-A-estrane-5-one is reacted with bromine in an inert solventand the 6 xi -bromo-11 Alpha -formyloxy-17 Beta-acyloxydes-A-estrane-5-one is dehydrobrominated with a mixture oflithium carbonate and lithium bromide.
 6. The process of claim 1 whereinthe 11 Alpha -formyloxy- 17 Beta -acyloxy-des-A- Delta 6-estrene-5-oneis reacted with an alkali selected from the group consisting of alkalimetal carbonates and bicarbonates in hot aqueous methanol.
 7. Theprocess of claim 1 wherein the 17 Beta -acyloxy-des-A-Delta 6-estrene-11Alpha -ol-5-one is reacted with a methyl magnesium halide in thepresence of a cuprous halide.
 8. The process of claim 1 wherein the 7Alpha -methyl-17 Beta -acyloxy-des-A-estrane-11 Alpha -ol-5-one isreacted with methane sulfonyl chloride to form 7 Alpha -methyl-11 Alpha-methane-sulfonyloxy-17 Beta -acyloxy-des-A-estrane-5-one which isreacted with lithium bromide in dimethylformamide.
 9. The process ofClaim 1 wherein the 7 Alpha -methyl-17 Beta -acyloxy-des-A- Delta9-estrene-5-one is reacted with an alkali metal hydroxide to form 7Alpha -methyl-des-A- Delta 9-estrene-17 Beta -ol-5-one which is thenoxidized with chromic anhydride.
 10. The process of claim 1 wherein 7Alpha -methyl-des-A- Delta 9-estrene-5,17-dione is reacted with acompound selected from the group consisting of pyrrolidine, piperidine,morpholine and dilower alkylamines and the resulting 5-enamino-7 Alpha-methyl-des-A- Delta 9-estrene-17-one is condensed with1,3-dichlorobutene-2in dimethylformamide in the presence of an alkalimetal iodide.
 11. The process of claim 1 wherein 7 Alpha-methyl-4,5-seco-Delta 9-estrene-3,5,17-trione is cyclized withpyrrolidine.
 12. The process of claim 1 wherein 7 Alpha -methyl- Delta5(10), 9(11)-estradeiene-3,17-dione is reacted with methanol in thepresence of hydrochloric acid.
 13. The process of claim 1 wherein the3-diloweralkoxy-7 Alpha -methyl- Delta 5(10),9(11)-estradiene-17-one isreacted with potassium acetylide.
 14. The process of claim 1 wherein 7Alpha -methyl-17 Alpha -X-Delta 5(10),9(11)-estradiene-17-ol-3-one isreacted with 2,3-dichloro-5,6-dicyano-p-benzoquinone.